Blood clotting, or coagulation, results from a sequence of reactions involving several proteins known as coagulation factors. Some of these factors have other names. For example, Factor I is also called fibrinogen, and Factor II is prothrombin. The liver produces these proteins and secretes them into the blood. Coagulation begins when some of the coagulation factors contact damaged tissue. Each factor reaction triggers the next reaction in a cascade. The final product of the coagulation cascade is a blood clot or a thrombus. The formation of a blood clot in a blood vessel (thrombosis) and its subsequent release (thromboembolism) can lead to grave medical conditions such as systemic embolism, stroke, and other blood clotting disorders.
Normally, the blood's ability to clot is a desirable characteristic. Some people, however, will develop conditions which may be negatively impacted by normal blood clotting. For example, people with certain types of irregular heart beat, people with prosthetic heart valves, or people who have suffered a heart attack are in danger of blood clots forming or growing larger in the blood and blood vessels. Such clots can lodge in the heart, lungs, or brain and cause strokes or even death in some cases. As treatment for people at risk of blood clotting disorders, physicians often prescribe oral anticoagulants such as warfarin or heparin. Other patients that can benefit from anticoagulants include cardiac patients, post-surgical patients, or trauma victims susceptible to thrombosis as a result of tissue and blood vessel damage. These patients are treated with anticoagulant therapy for a period of time after invasive surgery or trauma when they are most at risk.
The dosage of anti-clotting medication given to patients must be carefully determined. The anti-clotting medication is dosed based on the amount of clotting factors which are present in a person's blood. Coagulation can be strongly affected by diet or medication. For example, foods rich in vitamin K are well known to interact with the effects of prescribed anticoagulants. Variability in consumption of vitamin K containing foods such as green vegetables or vitamin supplements can deregulate the prescribed dosage, placing the patient in risk. The therapeutic range of blood coagulation is relatively narrow-outside this range, the patient can experience serious complications such as thromboembolism or, on the other extreme, hemorrhaging and internal bleeding. This problem is extensive in our society, leading to an estimated 300,000 deaths per year in the US alone.
A number of tests are performed in clinical laboratories to measure coagulation. Most are assays where the patient's blood is exposed to reagents that catalyze coagulation and thereafter, the time to reach a level of coagulation is monitored. The clotting time is then compared with a standard to obtain a relative ratio. The most widely used test of this type is the so-called prothrombin time assay or PT test. Unfortunately, due to the fact that coagulation agents such as fibrinogen are present primarily in blood, PT tests do not use other body fluids such as urine, interstitial, or lymph fluids. Consequently, coagulation testing is invasive and requires drawing blood. Although testing methods are improving that require lower blood volumes for analysis, all tests today require blood to be drawn.
As a result of fluctuations in clotting factors, patients on anti-coagulation therapy need to be routinely tested. Results from coagulation tests are of great value since they can provide preventive warning to the aforementioned complications and guide changes to the patient's dosage of oral anticoagulants. Depending on the stage and type of anticoagulant therapy, optimal test frequency can vary. Over ten million high risk surgical patients go on anticoagulation therapy in the US every year and are tested routinely at centralized laboratories associated with hospitals. Another three million people treated continuously with medication such as warfarin also require periodic testing. There is strong evidence that suggests coagulation testing every week or less can improve the ambulatory patient's ability to be within a safe therapeutic range. Due to the inconvenience of testing, however, testing compliance is often poor.
As mentioned, one type of coagulation test is called a prothrombin time (PT) test, which is a measure of the amount of time it takes blood to clot. Patients need to see a healthcare professional to have a PT test done. Blood must be drawn from the patient into a test tube, typically using a needle stick into a vein. The test tube usually contains an anticoagulant such as liquid citrate to keep the blood from coagulating prematurely. The blood sample is then mixed and centrifuged to separate blood cells from plasma. The plasma may then be analyzed on an instrument which takes a sample of the plasma. An excess of calcium is added to reverse the effect of the anti-coagulant, thereby enabling the blood to clot again. A tissue factor is added to simulate damaged tissue, and the time the sample takes to clot is measured optically. As a result of the number of skilled people who are involved in a PT test, as well as the equipment involved, the current prothrombin time (PT) test can be expensive. Additionally, a patient must often take the time to visit a laboratory for the test or coordinate a schedule with a visiting nurse. It can also take a significant amount of time to receive results from the test.
For an accurate prothrombin time measurement, the proportion of blood to citrate needs to be fixed. A preset amount of citrate (anticoagulant) is typically in each blood draw test tube. As a result, many laboratories will not perform the PT test if the sample tube of blood is underfilled. Therefore, in addition to being highly invasive, expensive, and time consuming, the PT test may require a relatively large sample of blood to be drawn each time the test is done.
Therefore, there is a need for a less expensive, less invasive, and more convenient prothrombin time test which encourages more frequent testing of blood clotting capability to assist health care professionals and patients in determining and adjusting the proper dosage of anti-clotting (or blood-thinning) medication. Such a test could also provide a more portable method used by the patient, in a point-of-care facility, or perhaps be administered directly by nursing staff or medical technicians.